Mechanisms of insulin secretion mediated by alpha cells

α细胞介导的胰岛素分泌机制

• 批准号: 10675549
• 负责人: Jonathan E Campbell
• 金额: $ 40.81万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10675549
• 关键词: Agonist; Alpha Cell; Animals; Area; B-Cell Antigen Receptor; B-Lymphocytes; Belief; Beta Cell; Cell Communication; Cell Line; Cell physiology; Cell secretion; Cells; Cellular Stress; Clinical; Compensation; Complement; Cyclic AMP; Data; Development; Diabetes Mellitus; Dimensions; Disease; Endocrine; Environment; Enzymes; Event; Fasting; Functional disorder; GLP-I receptor; Genes; Glucagon; Glucagon Receptor; Glucose; Glucose Intolerance; Goals; Health; Hepatic; High Fat Diet; Homeostasis; Hormones; Human; Hyperglycemia; Hypoglycemia; Impairment; Insulin; Interruption; Intervention; Islets of Langerhans; Ligands; Link; Maintenance; Mediating; Metabolic stress; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Paracrine Communication; Pathogenesis; Pathogenicity; Patients; Pattern; Peptide Receptor; Peptide Signal Sequences; Peptides; Phenotype; Physiological; Plasma; Population; Prevention; Production; Proprotein Convertase 1; Proprotein Convertase 2; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure of alpha Cell of islet; System; Testing; Tissues; Transcript; Work; antagonist; blood glucose regulation; cell type; diabetic; diabetic patient; driving force; drug development; effective therapy; experimental study; glucagon-like peptide; glucagon-like peptide 1; glucose production; glucose tolerance; human subject; hyperglucagonemia; impaired glucose tolerance; in vivo; insulin secretagogues; insulin secretion; islet; mouse model; novel; paracrine; pharmacologic; proglucagon; real-time images; receptor; response; therapeutic target; transcriptome sequencing; translational potential; translational study

Mechanisms of insulin secretion mediated by alpha cells Pancreatic islets contain multiple endocrine cells that produce hormones intimately involved in the control of glucose homeostasis. -cells, which secrete insulin, are both the most abundant cell type and the most studied cell type. -cell dysfunction leads to insufficient insulin production and ultimately hyperglycemia, the major pathophysiological phenotype of type 2 diabetes (T2D). -cells are the second most abundant cell type within islets, yet substantially less is known about -cell function or the role of these cells in glucose homeostasis. - cells secrete glucagon, which is canonically described as a hyperglycemic agent and an important counter- regulatory hormone in the prevention of hypoglycemia. -cell dysfunction is described as inappropriate glucagon secretion and is considered to be a driving force for hyperglycemia in T2D. However, glucagon receptors (GCGRs) are expressed on -cells and glucagon is a potent insulin secretagogue. Furthermore, it has been recently proposed that -cells synthesize and secrete glucagon-like peptide 1 (GLP-1), through alternative processing of the proglucagon gene transcript. GLP-1 receptors (GLP-1R) are also expressed on -cells, and GLP-1R agonists are currently available for use in T2D to increase insulin production. This raises the intriguing possibility that - to -cell paracrine interactions control insulin production and ultimately glucose homeostasis. Moreover, this perspective allows for the possibility that the increased glucagon secretion seen in T2D is a compensatory mechanism by which the -cells are attempting to increase -cell insulin production. Based on this, we hypothesize that increased -cell activity in T2D is not pathogenic per se, but rather, it is the interruption of - to -cell communication that results in decreased insulin production and hyperglycemia. Therefore, the overall goal of this project is to understand how -cells regulate -cell function, determine the importance of this relationship for normal glucose tolerance, and identify how severing the key node is pathogenic. We will accomplish this by first understanding the importance of - to -cell communication in the context of -cell function and overall glucose tolerance, and then determining if alterations in this axis occur during the development of -cell dysfunction. We will also define the relative importance of -cell glucagon versus GLP-1 production to delineate why -cells would produce two insulin secretagogues. Similarly, we will identify the importance of GCGR versus GLP-1R in -cells to determine if these are redundant systems or if they have unique roles in control of -cell function. This work will encompass cell lines and primary tissues, utilize novel mouse models, and determine the translational potential by conducting key experiments in human subjects in order to comprehensively understand the importance of - to -cell communication in normal and diabetic environments. Completion of this project will enhance our understanding of -cell function in order to identify how best to therapeutically target this cell type for the treatment of T2D.

由α细胞介导的胰岛素分泌机制 胰岛包含多个内分泌细胞，这些内分泌细胞产生密切涉及的激素 葡萄糖稳态。 细胞（秘密胰岛素）既是最丰富的细胞类型，也是研究最多的细胞类型 细胞类型。 细胞功能障碍导致胰岛素产生不足，最终导致高血糖症（主要） 2型糖尿病（T2D）的病理生理表型。 细胞是其中第二大细胞类型 胰岛，但对细胞功能或这些细胞在葡萄糖稳态中的作用知之甚少。 - - 细胞分泌胰高血糖素，胰高血糖素被典型地描述为高血糖剂，并且是重要的反质子 预防低血糖症的调节骑马。 细胞功能障碍被描述为不适当的胰高血糖素 分泌，被认为是T2D高血糖的推动力。但是，Glocagon接收器 （GCGRS）在细胞上表示，胰高血糖素是一种潜在的胰岛素促分泌物。此外，已经 最近提出细胞合成和秘密胰高血糖素样肽1（GLP-1），通过替代 proglucagon基因转录本的处理。 GLP-1受体（GLP-1R）也在细胞上表达，并且 GLP-1R激动剂目前可用于T2D，以增加胰岛素的产生。这引起了人们的吸引力 -至细胞旁分泌相互作用控制胰岛素产生并最终导致葡萄糖稳态。 此外，这种观点允许在T2D中看到的胰高血糖素分泌增加的可能性是 细胞试图增加细胞胰岛素产生的补偿机制。基于 这，我们假设T2D中增加的细胞活性本身不是致病性，而是中断 -到细胞通信导致胰岛素产生和高血糖降低。因此， 该项目的总体目标是了解细胞如何调节细胞功能，确定此的重要性 正常葡萄糖耐受性的关系，并确定几个关键节点是如何致病的。我们将 通过首先了解-在细胞的背景下的重要性来实现这一目标 功能和整体葡萄糖耐量，然后确定该轴上是否发生了变化 细胞功能障碍的发展。我们还将定义细胞胰高血糖素与GLP-1的相对重要性 生产以描绘为什么细胞会产生两个胰岛素促分子。同样，我们将确定 在细胞中GCGR与GLP-1R的重要性是确定这些是冗余系统还是它们是否具有 在控制细胞函数中的独特角色。这项工作将涵盖细胞系和主要组织，利用新颖 小鼠模型，并通过在人类受试者中进行关键实验来确定翻译潜力 为了全面了解-到细胞在正常和糖尿病中的重要性 环境。该项目的完成将增强我们对细胞功能的理解，以识别 如何最好地将这种细胞类型靶向T2D的治疗。